Species differences inN-dealkylation of oxamniquine

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Abstract
1. The major metabolite of the antischistosomal compounds desoxymansil (I) and oxamniquine (II) in various species is the 6-carboxylic acid (III). Mouse, rabbit, dog and monkey, but not rat, yield a second carboxylic acid metabolite (V) formed by oxidation of the isopropylaminomethyl side-chain. 2. Desoxymansil (I) incubated with microsomal preparations of rat, mouse or rabbit liver was metabolized to oxamniquine (II) by hydroxylation of the 6-methyl substituent; N-dealkylation of the isopropyl group did not occur. Oxamniquine (II) incubated with liver microsomal preparations did not undergo N-dealkylation, but the amine analogue (IV) of desoxymansil was deaminated by the liver microsomal preparations. 3. Oral administration of the amine analogue (IV) of desoxymansil to rat led to the excretion of the acid (V) in the urine, indicating that the rat can deaminate IV. Deamination of IV was shown to be catalysed by the mitochondrial fraction of liver, and mouse and rat showed similar levels of enzyme activity. 4. Intraperitoneal administration of desoxymansil to rat resulted in the biliary excretion of a conjugate of the alcohol (VI) but the acid (V) was not detected. 5. The anomalous metabolism of desoxymansil and oxamniquine in the rat is accounted for by two alternative metabolic pathways, namely, (i) N-dealkylation of the side-chain followed by oxidative deamination in the mitochondria and oxidation of the resultant aldehyde to the corresponding carboxylic acid, or (ii) oxidation of the α-carbon to give the carbinolamine which spontaneously decomposes in the cytosol to be subsequently reduced to the corresponding alcohol. The first pathway predominates in the mouse, rabbit, dog and monkey; the second pathway predominates in rat.